摘要:

AbstractThe effect of interferon alfa (IFN‐α) therapy on the expression of transforming growth factor alpha (TGF‐α) in the liver during chronic hepatitis B was investigated. Serial liver biopsy specimens were evaluated from 35 patients who had participated in a randomized, controlled trial of recombinant human IFN‐α for the treatment of chronic hepatitis B. Percutaneous liver biopsy specimens obtained before and 1 year after entry in the trial were sectioned and stained with a monoclonal antibody to TGF‐α in an avidin‐biotin‐peroxidase‐complex system. The expression of TGF‐α in each section was evaluated blindly (with respect to treatment group and order of biopsies) and was numerically scored. There was no significant difference in TGF‐α expression before or after therapy between 13 patients receiving daily IFN‐α, 13 receiving alternate‐day IFN‐α, and 9 receiving no therapy. Sustained clearance of HBV‐DNA and DNA polymerase activity occurred in 8 of 26 treated patients (“responders”); the 18 other patients were “nonresponders.” Expression of TGF‐α before IFN‐α therapy was significantly higher in responders than in nonresponders; after IFN‐α therapy, TGF‐α expression decreased significantly among responders compared with nonresponders and untreated controls. Thus, the level of expression of TGF‐α in the liver, which was correlated with the severity of inflammation in the liver in this study, appeared to be predictive of the response to IFN‐α therapy in chronic hepatitis B, with a higher level of expression indicating a greater likelihood that

ISSN:0270-9139    

DOI:10.1002/hep.1840220402

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractCharacteristics of 205 consecutive patients with hepatocellular carcinoma (HCC) admitted during 1990 to 1993 have been analyzed from the standpoint of hepatitis viral infection in Japan. Among 205 HCC patients, 71% of the patients showed positivity for hepatic C virus (HCV) antibody alone, 13% showed positivity both for HCV and HBV (HCV/HBV) antibody, 11% demonstrated HBsAg alone, and negativity of both HCV and HBV antibody in 4% only. Positivity to both HCV antibody and HBsAg was demonstrated in 1% only. Mean detection age of HCVAb‐positive HCC as well as both HCV/HBV antibody‐positive HCC was 62 ± 7 years, in contrast to 52 ± 13 years in HCC with HBsAg (P<.05). Male‐to‐female ratio among HCVAb‐positive HCC was 3.3:1, in contrast to 5.5:1 among the HCV/HBVAb‐positive HCC and 7:1 among HBsAg‐positive HCC, but there was no significant difference in the gender distribution between these groups. More than 60% of HCVAb‐positive HCC were classified into the stage of Child B and C, whereas 65% of HBsAg‐positive HCC was at the stage of Child A. The severity of liver disease was confirmed by liver histology, indicating that more than 70% of the HCVAb‐positive HCC and the HCV/HBVAb‐positive HCC showed cirrhosis, in contrast to 50% among the HBsAg‐positive HCC. Three‐year survival rate of HCV Ab‐positive HCC and HBV/HCVAb‐positive HCC was 68% and 56%, respectively, in contrast to 47% in HBsAg‐positive HCC. HCC was found at early stage among the patients receiving periodic medical checkups beforehand, and the prognosis of these HCC patients was significantly better than those who did not receive checkups. From these results, HCV‐related HCC occupied over 80% of total HCC in Japan, which are characterized by older age and more severe cirrhosis, as compared with HBsAg‐positive HCC. Prognosis of HCV Ab‐positive HCC was not significantly better than HBsAg‐positive HCC, but the periodical screening naturally improves prognosis because the cases are found usually much earlier (lead time bias) and mostly belong to slow progression type (leng

ISSN:0270-9139    

DOI:10.1002/hep.1840220403

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractWe used an anchor polymerase chain reaction method to compare the repertoires of transcribed T‐cell receptor β chain variable region (Vβ) genes in cord blood T cells from neonates of hepatitis B surface antigen (HBsAg) positive (n = 40) and HBsAg negative (n = 40) women. Fifteen of the HBsAg positive women were hepatitis B e antigen (HBeAg) positive, and 25 were HBeAg negative. The percentage of Vβ.4 transcripts was lower in cord blood T cells from neonates of HBsAg‐positive relative to HBsAg‐negative women (9.7% ± 0.5% vs. 12.7% ± 0.6%, P = .002). The percent of Vβ5.1 transcripts was higher in cord blood T cells from neonates of HBeAg‐positive relative to HBeAg‐negative women (9.3% ± 0.7% vs. 7.0% ± 0.3%,P<.001). There were no correlations between neonatal maturity at birth and Vβ repertoire. In summary, a maternal chronic hepatitis B virus (HBV) infection is associated with changes in the repertoire of transcribed T‐cell receptor genes in neonatal cord blood T cells. It is possible that the T‐cell response to the HBV is associated with a limited repertoire of Vβ genes. The mechanism of vertical chronic HBV infection in human neonates may involve changes in the T‐cell response to the virus that are inducedin utero. (HEPAT

ISSN:0270-9139    

DOI:10.1002/hep.1840220404

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractThe T helper (Th) cell response to hepatitis B core antigen (HBcAg) was analyzed in 76 chronic hepatitis B virus (HBV) carriers with varying degrees of hepatic inflammation and HBV replication. Fifty‐five patients had active viral replication, 28 with minimal histological changes and normal alanine transaminase (ALT) and 27 with active hepatic inflammation and elevated ALT. The remaining 21 chronic hepatitis B surface antigen (HBsAg) carriers had undetectable HBV replication, minimal histological activity, and normal ALT. In addition, 34 chronic HBV carriers were studied prospectively during treatment with α‐interferon. The HBcAg‐specific Th cell response was evaluated by a proliferative assay using3H‐thymidine uptake and γ‐interferon production by peripheral blood mononuclear cells. The proliferative response and γ‐interferon production of patients with active hepatic inflammation were significantly higher than in patients with minimal histological changes and in controls. In the longitudinal analysis during α‐interferon treatment, 22 of 34 patients sustained an ALT flare accompanied by a parallel, significant Th cell response, which preceded or coincided with the ALT flare. The elevation in the Th cell response and the ALT flare were followed by a significant rise in the serum immunoglobulin (Ig) M anti‐HBc index. Ten of twenty‐two patients with an enhanced Th cell response and an ALT flare seroconverted after α‐interferon treatment. The Th cell activity in the 10 responders rapidly subsided after hepatitis B e antigen (HBeAg) to anti‐HBe seroconversion, whereas in the 12 nonresponders it remained elevated. This study demonstrates that patients with chronic hepatitis B (CAHB) have a detectable and a significant Th cell response to HBcAg, which is likely to be involved in augmenting the immune‐mediated hepatocellular damage and in the activation of HBV‐specific humoral immune reaction. Thus, loss of Th cell nonresponsiveness to HBcAg is an important factor in enhancing the effector immune responses to HBV in chronic hepatitis B. (

ISSN:0270-9139    

DOI:10.1002/hep.1840220405

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractThe aim of the study was to determine the respective influence of pretreatment serum hepatitis C virus (HCV) RNA levels and HCV genotype on the response to interferon (IFN) alfa in patients with chronic hepatitis C. We retrospectively studied 141 patients with chronic hepatitis C included in two consecutive controlled trials of IFN alfa. A sustained response was observed in 28, a response followed by relapse in 43, and no response in 70 patients. Pretreatment serum HCV RNA quantitation with the branched DNA (bDNA) assay and HCV genotyping with reverse hybridization assay (LiPA) were performed in all patients. Seventy‐four percent of the patients had detectable serum HCV RNA (43%, 77% and 84%) in the three groups of patients with sustained response, relapse, and no response, respectively (P= .005). Mean serum HCV RNA level were 1.4 ± 6 × 106, 4.8 ± 6 × 106, and 3.9 ± 5 × 106genomes/mL in patients with sustained response, response and relapse, and no response, respectively (P<.01). Genotype 1b was found in 7%, 47%, and 46% of the patients in the three response groups, respectively. By univariate analysis, age, source, and duration of HCV infection, serum HCV RNA levels, and HCV genotypes were significantly different in the three response groups. By multivariate analysis, the only independent factors associated with sustained response were low serum HCV RNA levels and HCV genotype other than 1b. Pretreatment serum HCV RNA levels and HCV genotype are the main and independent factors associated with sustained response to IFN therapy. (HEPATOLOGY1995; 22:1050

ISSN:0270-9139    

DOI:10.1002/hep.1840220406

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractEvidence suggests that cellular immunity to hepatitis C virus (HCV) core protein may be important in the pathogenesis of viral infection. Therefore, interferon gamma (IFN‐γ) production by peripheral blood mononuclear cells (PBMC) derived from patients with chronic HCV infection (genotype 1b) was examined. The cellular immune response was evaluated with a recombinant HCV core fusion protein derived from a patient with genotype 1b. To identify the immunodominant epitopes, IFN‐γ production in responders was also assessed with a panel of nine synthetic peptides that covered the entire core region. It was found that mononuclear cells from 24 (52%) of 46 patients with chronic liver disease responded to the core protein; asymptomatic HCV carriers demonstrated a lower response rate (14%,P<.05). More important, individuals who had received IFN‐α treatment and went into clinical and virological remission had a higher response rate (75%,P<.05) compared with those with ongoing hepatitis whose treatment failed (31%). Of 25 patients whose mononuclear cells responded to HCV core protein, 18 had a significant response to one or more peptides; 12 patients reacted to a peptide mixture containing hydrophilic sequences. The core peptide amino acid sequence 141 to 160 was recognized in 9 patients. Interestingly, 7 of 8 patients bearing HLA DR 4 and w53 haplotypes recognized the peptide sequence 141 to 160. Thus, IFN‐γ production of the mononuclear cell response appeared to be HLA DR restricted, and the responding cells were identified as CD4+T cells. This study suggests the presence of immunodominant T cell epitopes within the HCV core protein in association with HLA DR phenotypes in patients with HCV‐associated liver disease. (HEPATOLOGY1995;2

ISSN:0270-9139    

DOI:10.1002/hep.1840220407

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractTo determine whether hepatic metabolic function affects the response to interferon treatment, we measured antipyrine clearance (APC) in 85 patients with chronic active hepatitis C and compared the results with treatment outcome. Among 55 patients who responded to interferon by normalization of alanine transaminase (ALT), median APC before treatment was 0.47 (range, 0.12 to 0.98; normal range, 0.34 to 1.02 mL/min/kg body wt), a value that was significantly greater than in 30 nonresponders (0.23; 0.08 to 0.67 mL/min/kg body wt,P0.25 mL/min/kg body weight had an 85% chance of responding to interferon; this was unlikely a simple reflection of histological activity, because the correlation with Scheuer score was poor in this subgroup (r= ‐.31,P<.05). A second, independent group of 43 patients was used to test the predictive value of APC (using 0.25 mL/min/kg body wt as a cut‐off) for response to interferon treatment. In this group, APC correctly predicted positive response to interferon in 75% of cases. APC was also used to measure the effects of treatment on hepatic metabolic function. Regardless of outcome, there was no change in APC at the end of a 6‐month course of interferon treatment. Six months later, however, improvement in APC (14%;P<.05) was evident among responders but not in those who had failed to respond to interferon. In patients who continued to have normal ALT (18 of 19 tested were also nonviremic), the improvement in APC was sustained for at least 24 months, whereas among relapsers (defined by ALT increase), APC eventually declined to be less than the pretreatment value at 24 months. It is concluded that pretreatment APC is a powerful positive predictor of responsiveness to interferon treatment in patients with chronic hepatitis C, indicating that good hepatic metabolic function may be important in determining the effectiveness of interferon treatment. Furthermore, changes in hepatic metabolic function after apparently successful treatment, at least as determined by APC, appear to be subtle, delayed in onset, and maintained only in those who remain in biochemical remission. (HEPATOLOGY1995; 22:1065

ISSN:0270-9139    

DOI:10.1002/hep.1840220408

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractWe prepared a hepatotropic conjugate, suitable for intramuscular (IM) injection, of lactosaminated poly‐Llysine with adenine arabinoside monophosphate (ara‐AMP), a drug active against hepatitis B virus (HBV). We studied its organ distribution in mice and its antiviral activity in woodchucks that are carriers of woodchuck hepatitis virus (WHV). In mice, after IM administration of a conjugate tritiated in the drug moiety (5.2 μg/g equal to 2 μg/g of ara‐AMP) radioactivity in liver was three times greater than in kidney, spleen, and intestine. On the contrary, after IM injection of unconjugated, tritiated, are‐AMP (5 μg/g) the amounts of radioactivity in liver, spleen, and kidney were similar. Unconjugated ara‐AMP and the conjugate were administered IM to woodchucks for 13 days. Unconjugated ara‐AMP decreased viremia at the daily dose of 5 mg/kg but was ineffective at 2.5 mg/kg. The conjugate at the daily doses of 4.2 and 7 mg/kg (equal to 1.5 and 2.5 mg/kg of ara‐AMP, respectively) markedly lowered the viremia, which decreased to undetectable levels in the animals treated with the higher dose. Assuming that in HBV‐infected patients the same doses will be active, then the amount of conjugate (soluble at 200 mg/mL) required by a 70‐kg patient will be contained in a volume of 1.5 to 2.5 mL, compatible with the IM route. Compared with a similar ara‐AMP complex with lactosaminated human albumin, currently being studied in clinical trials for the treatment of chronic type B hepatitis, which must be infused intravenously, the present conjugate might provide more patient compliance because of IM administration. (HEPATOLO

ISSN:0270-9139    

DOI:10.1002/hep.1840220409

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractTwo human monoclonal antibodies with anti‐hepatitis B activity were investigated separately and as a mixture by means of an “inhibition in solution” assay. With this assay the capacity of anti‐HBs antibodies to inhibit the binding of hepatitis B surface antigen (HBsAg) with solid‐phase anti‐HBs (Ausria II, Abbott Laboratories) was studied. Both HBsAg of different subtypes and purified Dane particles were used. One of the monoclonal antibodies (9H9) was directed against a conformational epitope (anti‐“a” like) but induced incomplete inhibition (80% to 90%) of all HBsAg subtypes; the other (4–7B), active against a linear epitope, caused full inhibition of all HBsAg subtypes except one (HBsAg/adw4).In vitro, a mixture of these two monoclonal antibodies was active against HBsAg from liver transplant recipients, including those with suspected variant viruses. (HEPATOLOGY1

ISSN:0270-9139    

DOI:10.1002/hep.1840220410

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractThe aim of this open trial was to assess the efficacy and the safety of interferon (IFN) alfa therapy in liver transplant recipients with chronic active hepatitis caused by hepatitis C virus. In July 1991, among 447 liver recipients regularly observed at our institution, 46 had developed HCV‐related chronic active hepatitis defined by piece meal necrosis. Fourteen of these 46 patients received IFN alfa 3 mIU three times weekly for a planned duration of 6 months and were compared to the 32 untreated patients. Genotyping and quantification of viremia were performed using type‐specific amplification and branched DNA assay. Histological follow‐up was available in all patients and routinely before and after IFN therapy. Treated and untreated patients did not differ regarding gender, age, length of follow‐up, maximum histological score, and genotypes (41 of 46 were of type 1b). Induction of chronic rejection was observed in 5 of 14 treated patients leading to retransplantation in 3. In contrast, chronic rejection occurred in 1 of 32 untreated patients (P<.005) during the posttransplantation follow‐up. Among the 9 treated patients without rejection, a decrease of transaminases or of HCV RNA levels of more than 50% were observed in 8 and 4, respectively; 2 patients had a complete response, and 1 did not relapse after discontinuation of IFN. Histological improvement occurred in 2 of the treated patients and in none of the untreated patients. IFN therapy in liver transplant recipients has poor antiviral effect and can induce chronic rejection. Its use in this setting should be cautious. (HEPATOLOGY1995; 22:10

ISSN:0270-9139    

DOI:10.1002/hep.1840220411

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY